Epilepsy is a chronic condition of spontaneous recurrent seizures that affects about 1% of our population. Although treatment is successful for most patients, one third remain uncontrolled on any of the available medications. Mesial temporal lobe or limbic epilepsy is one of the most common forms of therapy resistant epilepsy. Understanding the basis for this disorder is necessary for the development of more effective therapies. Anatomically this syndrome involves the primary limbic structures such as the hippocampus, amygdala and entorhinal cortex. There is growing evidence for the involvement of subcortical structures in this syndrome as well, and one site of interest is the midline nuclei of the thalamus, including the medial dorsal nucleus and the rhomboid/reuniens complex, which have strong connections to and from the limbic structures. This region shows clear anatomic changes in human imaging studies and in pathology studies in animal models. In the current funding period we have found that the midline thalamus is consistently involved in limbic seizures from the onset, suggesting that this area is part of the primary seizure circuit. In addition we have good evidence that the midline is capable of modulating seizure severity and duration. In this proposal we wish to build on these past findings and examine the means by which this region modulates seizure activity with a focus on the role of GABA, the inhibitory neurotransmitter. In this project we will use two models of limbic seizures and epilepsy to examine three specific questions: 1) Can GABA and its many agonists modulate seizure activity when administered to specific sites in the thalamus? 2) Can the synaptic input from the limbic sites to the midline thalamus, one arm of the hypothesized thalamolimbic seizure loop, be influenced by GABA and its agonists? 3) Are there specific alterations in the pharmacology and physiology of GABA in limbic epilepsy that affect the efficacy of GABA? By focusing on the role of GABA and its modulators in the midline thalamic region, we hope to determine first whether this subcortical area with broad reciprocal limbic connections is a potential target for seizure suppressing therapy, and whether GABA enhancing agents directed to this region can be useful therapeutic agents.